FIBROBLAST DIFFERENTIATION IN WOUND HEALING

伤口愈合中的成纤维细胞分化

• 批准号: 7085798
• 负责人: JAMES J TOMASEK
• 金额: $ 8.01万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7085798
• 关键词: DNA footprinting; actins; binding proteins; cell differentiation; cytoskeletal proteins; fibroblasts; gel mobility shift assay; gene expression; gene targeting; genetic promoter element; genetic regulation; genetically modified animals; interferon gamma; laboratory mouse; nucleoproteins; protein structure function; recombinase; smooth muscle; southern blotting; tissue /cell culture; transfection; transforming growth factors; wound healing

EXCEED THE SPACE PROVIDED. Tissue contraction is an integral part of wound closure; however, excessive or abnormal contraction of tissues can lead to pathological contractures, tissue deformation and loss of tissue function, all major health problems in the United States. The long-term goal of this project is to understand the cellular basis underlying wound contraction and tissue contracture by studying the formation and function of the myofibroblast. Myofibroblasts are specialized fibroblasts that express smooth muscle alpha-actin (SMAA) and assemble contractile structural elements as part of their ability to generate the contractile force responsible for tissue contraction. Our recent studies have demonstrated that the mechanical properties of the extracellular matrix are critical in regulating SMAA expression and myofibroblastformation and function. These results have led to a series of novel hypothesis regarding mechano-regulation of myofibroblast formation and function: (i) mechano-regulation of the SMAA promoter in myofibroblasts is mediated by changes in actin dynamics; (ii)myocardin-related transcription factor A (MRTF-A) couples mechano- regulated changes in actin dynamics with gene expression by translocating from cytoplasmic actin to the nucleus; (iii) MRTF-A activates a subset of SM-specific cytoskeletal proteins, in addition to SMAA, in myofibroblasts; (iv) MRTF-A activation of this subset of SM-specificcytoskeletalproteins is responsible for assembly of functional contractile structural elements and contractile force generation in myofibroblasts. We will test these hypotheses by use of various types of three-dimensional collagen lattices that we have demonstrated can provide different mechanical environments and mimic the process of wound contraction. It is our hope that an understanding of the mechanism of mechano-regulation of myofibroblast formation and function will provide future opportunities for targeting specific signaling pathways and transcriptional regulatory events to regulate wound healing and pathological contractures. PERFORMANCE SITE ========================================Section End===========================================

超出所提供的空间。组织收缩是伤口闭合的一个组成部分；然而，组织过度或异常收缩可能导致病理性挛缩、组织变形和组织功能丧失，这些都是美国的主要健康问题。该项目的长期目标是通过研究肌成纤维细胞的形成和功能来了解伤口收缩和组织挛缩的细胞基础。肌成纤维细胞是表达平滑肌α-肌动蛋白（SMAA）并组装收缩结构元件的特殊成纤维细胞，作为其产生负责组织收缩的收缩力的能力的一部分。我们最近的研究表明，细胞外基质的机械特性对于调节 SMAA 表达以及肌成纤维细胞的形成和功能至关重要。这些结果引发了一系列关于肌成纤维细胞形成和功能的机械调节的新假设：（i）肌成纤维细胞中 SMAA 启动子的机械调节是由肌动蛋白动力学的变化介导的； (ii) 心肌素相关转录因子 A (MRTF-A) 通过从细胞质肌动蛋白易位到细胞核，将肌动蛋白动力学的机械调节变化与基因表达结合起来； (iii) MRTF-A 除了 SMAA 之外，还激活肌成纤维细胞中的 SM 特异性细胞骨架蛋白子集； (iv) MRTF-A 激活 SM 特异性细胞骨架蛋白，负责肌成纤维细胞中功能性收缩结构元件的组装和收缩力的产生。我们将通过使用各种类型的三维胶原蛋白晶格来测试这些假设，我们已经证明这些三维胶原蛋白晶格可以提供不同的机械环境并模拟伤口收缩的过程。我们希望，对肌成纤维细胞形成和功能的机械调节机制的了解将为未来针对特定信号通路和转录调节事件来调节伤口愈合和病理性挛缩提供机会。表演网站==========================================部分结束====== =======================================